In December 2013 I wrote about a
leading Italian researcher and clinician called Professor
Antonio Persico and gave a link to an excellent presentation he gave in the US,
about his views on the underlying biological process behind autism.
He had a nice graphic in which he
depicted the puzzle that is autism.
One of his findings was that
in the autistic brain there is an excess of both physical calcium and calcium
signaling (via ion channels). He did not draw any therapeutic conclusions,
which as I said was a pity.
In fact, Persico is far from the
first scientist to point the finger at calcium channelopathies.
A few months before this, I had decided
I would apply myself to see if there were any safe, practical therapies that
could be applied, based on all the scientific research about calcium ion
channels; incomplete as it might be.
After a few hours, or so, of reading
about the biology of calcium channels, the available drugs and the existing
research in their use in conditions other than autism, I came to the conclusion
that Verapamil looked a very likely candidate.
Verapamil is a so-called L-type
calcium channel blocker (L representing
long-lasting length of activation); it particularly affects a type
of voltage-gated calcium channel called Cav1.2.
For various reasons, I had deduced that these Cav1.2 channels were
possible open more often than they should be in the brain of Monty, aged 10
with ASD. I proposed that over
activation of these channels resulted in extreme agitation that leads to
aggression and self-injurious behavior in autism.
Back in September 2013, Monty was
still having behavioral problems, apparently brought about by summertime pollen
allergies. I did write extensively about
this and how I had narrowed the problem down to mast cell degranulation and histamine. Treating the allergy did a lot of good, but
was never a complete solution, since the standard allergy drugs worked for only
a couple of hours, rather than the 24 hours they claimed.
So I had Monty in a state of near
explosion by mid-afternoon most days, with a red face and letting us all know
he was not feeling good. He would say
things including “be nice”, “I want to be nice”, “to hit your head” or even, on
a good day, “to hit your head and see birdies”.
By then, he was also having Rupatadine, a mast cell stabilizer, which
did seem to help. The eruptions were far
less often and less severe than in July, but it was clear that more could be
done.
One afternoon, I decided to give a
very small dose (20mg) of Verapamil, and before my eyes, the anger and
agitation began to fade and was replaced by calm. It was the most amazing experiment that I
have witnessed and within 20 minutes there was complete calm.
In the following weeks, I would still
hear Monty say “be nice”, but this was no longer followed by any aggressive
behaviour. The trigger was still there
to energize these channels, but they had blocked by Verapamil. It was like firing a gun, but with no
ammunition; there was a “click”, but no “bang”.
This is the reason that Verapamil is
in the PolyPill, in case anyone has wondered.
Before you start googling, there is
absolutely no published research to support the use of Verapamil in
autism. This is part of the reason I did
not to write about it at the time.
Verapamil is also a blocker of certain
voltage-gated potassium channels and has the effect of raising potassium levels
in the blood. We have seen in earlier
posts that potassium channel dysfunction is also present in autism and that
raising potassium levels helps reduce sensory overload. One effect of bumetanide is that it lowers
levels of potassium, so bumetanide and verapamil are in that way very complementary.
Subsequently, I have read that
mutation of the CACNA1C gene is associated with schizophrenia, which is like adult-onset autism. The
calcium channel produced from the CACNA1C gene is
Cav1.2. So this might be a case of what
helps in autism might help in schizophrenia.
If you are interested in why I
decided to test Verapamil, read on.
Observations
Anger
& SIB
Anger, leading to violence against
others and to yourself are behaviours that arise in many people with
autism. There are undoubtedly many
causes, and many are behavioral. If a
non-verbal person cannot express what he wants, or a partially verbal child has
some pain (e.g. toothache) and does not understand it, things are likely to get
out of control.
But there are other times, when for
no apparent reason, nasty behaviour can occur, so I presumed that there might
be a biological explanation. If there
was one, then I would think about a biological intervention.
My wife always asked Monty if his
head was hurting when these kinds of behaviors popped up. He would usually say “yes”, but it could well
have been to avoid any other questions. But
why not consider it as possible that there is a pain prior to SIB.
Fever
Effect
Then we have the recurring
observation about autistic behaviours changing when the person has a high
temperature; the fever effect. This has
now been studied by literally warming people up in hot water and then carrying
out behavioural test.
As usual in autism, this effect
applies much more to some people than to others. Monty is moderately affected, but some people
are dramatically improved.
Headaches
Headaches are very common, but some
people do seem to get far more than their fair share. Migraines are particular nasty and so is
another type, the cluster headache.
Cluster headaches are severe headaches
that are clustered together.
Cluster headaches are occasionally referred to as
"alarm clock headaches" because of the regularity of their timing and
they may awaken individuals from sleep. Both individual attacks and the cluster
grouping can have a metronomic regularity; attacks striking at a precise time
of day each morning or night is typical. This has prompted researchers to
speculate involvement, or dysfunction of the brain's hypothalamus, which
controls the body's "biological clock" and circadian rhythm.
Now I have noted that in some literature it is claimed
that parents of children with autism often have a history of headaches (and I
do not mean caused by dealing with their child’s autism).
Note that most younger people with autism have a “faulty”
biological clock, so they have trouble sleeping through the night.
Febrile
seizures
Seizures and autism are closely
related. Febrile seizures occur in some
children when they have a temperature greater than 38 °C (100.4 °F). They are twice as common in Japanese children
than they are in Western children, occurring in up to 9% of children and mainly
in boys.
It is not agreed exactly what causes
febrile seizures, Japanese research points to voltage-gated sodium channels,
which does not really support my theory.
However, rather than delete this part of the post, I did a little more
digging and found a paper in the Journal of Neuroscience that does neatly fit
by theory.
Comorbidities
It is well documented that poor
cardiac health is associated with autism.
I have commented before that it is not entirely by coincidence that some
drugs that help autism were actually developed as drugs for heart problems. By treating the autism, a side benefit is
that you may also be treating (and perhaps avoiding) the heart disease that
would otherwise likely to develop at quite a young age.
So, while giving statins and calcium
channel blockers to a healthy young person would be irresponsible, the same may
not true for people with autism. In the
same way that people with type 1 diabetes have been recognized as being at high
risk of heart disease and are put on preventative drugs at a much younger age
than the wider public. Patients with type 1 diabetes are 10 times more at risk from
heart disease than other healthy patients.
They are recommended statins, aspirin therapy and an ACE inhibitor. An ACE inhibitor reduces blood pressure in a
different way to how Verapamil also lowers blood pressure.
Due to the severity of
neurological/behavioral problems of autism, medical practitioners are not really
worrying about cardiac health.
Too
Much Calcium
There are opposing views about the
role of vitamin D in autism; in other words, too much or too little. There have been some interesting thoughts
about milk and autism, and not about whether or not it is fortified with extra
vitamin D; the point was the role played by calcium.
Then there is the mother who found
that supplementing her autistic child with calcium had some frightening consequences,
producing profound regression.
Basic
Biology
If you want to read about the basic
biology of calcium channels, here are links to Wikipedia;-
Connections
with the biology
One of the things that drew my
attention was the fact that the behaviour of some calcium channels is
temperature dependent. There are other
ion channels that are also temperature dependent. The Cav1.2 channels are known to behave
differently according to their temperature.
Connections
within the literature
Timothy syndrome
I have covered Timothy syndrome
previously in this blog.
This is a, thankfully, extremely rare
condition in which the most people do not survive to childhood; those few that
do are likely to have autistic-like symptoms.
The syndrome is caused by severe
mutations of the CACNA1C gene. As a result it is also associated with severe
heart problems, since this gene expresses the Cav1.2 channel that is found in
the heart and the brain.
In the following
article, Dr Ricardo Dolmetsch used an experimental L-type calcium channel
blocker, called Roscovitine, to
“successfully” treat his model of Timothy Syndrome.
Dolmetsch is now
Head of
Neuroscience at the Novartis Institute for Biomedical Research. I did write to him once, when he was still at
Stanford, to ask if he was interested in discussing some of my ideas – no
answer, I guess he was busy curing autism.
Headaches
It has been known for many years that some L-type calcium channel blockers are effective in treating both migraine headaches and cluster headaches.
Individualizing treatment with verapamil for cluster headache patients
CONCLUSIONS:
Providing the dosage for each individual is adequate, preventing
CH with verapamil is highly effective, taken three (occasionally with higher
doses, four) times a day. In the majority (94%) with episodic CH steady dose
increase under supervision, totally suppressed attacks. However in the chronic
variety only 55% were completely relieved, 69% men, but only 20% women. In both
groups, for those with partial attack suppression, additional prophylactic
drugs or acute treatment was necessary.
This study found that some people required 5 times
higher dose than others and doses were up to 960mg per day.
Verapamil in prophylactic therapy of migraine
We conducted a double-blind, placebo-controlled
crossover study of verapamil HCI in the prophylaxis of chronic migraine
headaches. Verapamil significantly reduced both headache frequency and duration
with few side effects. The drug may be useful for a segment of the migraine
population refractory to other prophylactic agents or for those who cannot
tolerate the side effects of other drugs
Mice and SIB (Self Injurious Behaviour)
Lots of people do not like the idea of
being compared to mice, or even worse rats.
Nonetheless, this following paper is indeed very relevant, it showed
that it you active the L type calcium channels in mice they will engage in self
injurious behaviour.
The L type calcium
channel agonist Bay K 8644 has been reported to cause characteristic motor
abnormalities in adult mice. The current study shows that administration of
this drug can also cause the unusual phenomenon of self-injurious biting, particularly when given to young mice.
The self-biting
provoked by Bay K 8644 can be inhibited by pretreating the mice with dihydropyridine
L type calcium channel antagonists such as nifedipine, nimodipine, or
nitrendipine.
However, self-biting
is not inhibited by nondihydropyridine antagonists including diltiazem, flunarizine,
or verapamil.
If
Monty was a mouse, verapamil would therefore likely not work and I would
probably have had to use nimodipine.
Genes
I do not claim to
be an expert in Genetics, but I can uses genes to support my case.
In 2013 a paper was
published in the Lancet that looked for genetic links between a range of
neurological disorders.
In this paper you
can find out many things, including:-
- Gain-of-function mutations in CACNA1C causes Timothy syndrome
- CACNA1C is a susceptibility gene for bipolar disorder, schizophrenia, and major depressive disorder
- neuroimaging studies have documented effects of CACNA1C variants on a range of structural and functional brain phenotypes, including circuitry involved in emotion processing, executive function, attention, and memory
- Mutation in the CACNB2 gene are associated with Brugada syndrome, autism, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and schizophrenia
- CACNB2 encodes an auxiliary voltage-gated calcium-channel subunit that interacts with L-type calcium-channel subunits (including CACNA1C, CACNA1D, and CACNA1S) to promote their trafficking to the plasma membrane, increase their function, and regulate their modulation by other signaling proteins and molecules
Now “my” Calcium channel, also known as Cav1.2, is
encoded by the very same CACNA1C
gene.
In a similar paper,
autism also gets a mention
“Genetic variation in CACNA1C have also been associated with
depression, schizophrenia, autism spectrum disorders”
So all in all the
genetic analysis also point to Cav1.2 as a good candidate for some
intervention.
Epilepsy
Verapamil is being
investigated to treat various forms of epilepsy and seizure. This is interesting, since seizures are
highly comorbid with autism.
Seizures tend to
develop in early puberty in many cases of autism. It appears possible (maybe not probable) that
if you can avoid the onset of epilepsy during this time of hormonal change, you
may be free of it for life. The science
has shown that the first seizure makes a biological change occur; the same is indeed true with asthma. If you can identify the at risk group (i.e.
people with autism for epilepsy and atopic dermatitis for asthma) you may indeed
be able to avoid it.
I was not aware of
this until after Monty, aged 10 with ASD, had developed asthma, but I am well
aware of it now. I am actively taking
steps to avoid epilepsy.
The other useful
aspect of this research is that they are all clinical trials of Verapamil in
children. This is important from the
safety perspective.
Choice of Channel Blocker
In medicine,
calcium channel blockers were developed to treat heart conditions. A common problem in treating autism is the
need for drugs to freely cross the blood barrier (BBB); most do not.
Other issues
include the half-life of the drug and most importantly the safety of the drug.
Given these
considerations, and the fact that I know precisely which calcium channel I want
to block, this led to me to Verapamil.
It is very widely
used, and is available very cheaply as a generic in sizes down to 40mg. Adult and indeed child dosages go all the way
up to 400+mg a day.
Since the idea is
to subtly affect the brain and not dilate blood vessels in
the heart, which increases the supply of blood and oxygen; a small dose was
envisaged, 20 mg.
On paper,
Nimodipine, also looks a very interesting candidate, but it is rarely used in
children. It would be useful to trial it
on adults with autism. It works better
than verapamil in mice with SIB.
Conclusion
I must admit that
some of my “evidence” was gathered after I had proved my theory was valid, like
the mice with SIB after their L-type channels were activated.
Given all of the
“evidence” it does amaze me that it did not occur to anyone to try a drug like
Verapamil in children with autism.
Clearly all drugs
carry a risk, but so does violence and self-injury.
P.S. Note that magnesium is also a calcium channel blocker
